Abstract
The hexadehydro-Diels-Alder (HDDA) cascade enables the synthesis of complex benzenoid products with various substitution patterns through aryne intermediates. The first stage of this cascade involves the generation of a highly reactive ortho-benzyne intermediate by a net [4+2] cycloisomerization of a triyne substrate. The benzyne can be rapidly 'trapped' either intramolecularly or intermolecularly with myriad nucleophilic or π-bond-donating reactants. As a representative example of a general procedure for synthesizing highly substituted benzenoids, this protocol describes the synthesis of a typical triyne substrate and its use as the reactant in an HDDA cascade to form a phthalide. The synthetic procedure detailed herein (four chemical reactions) takes 16–20 h of active effort over a period of several days for the preparation of the triyne precursor and ∼2 h of active effort over a 3-d period for the generation and trapping of the benzyne and isolation of the phthalide product.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Himeshima, Y., Sonoda, T. & Kobayashi, H. Fluoride-induced 1,2-elimination of o-trimethylsilylphenyl triflate to benzyne under mild conditions. Chem. Lett. 12, 1211–1214 (1983).
Miyawaki, K., Suzuki, R., Kawano, T. & Ueda, I. Cycloaromatization of a non-conjugated polyenyne system: synthesis of 5H-benzo[d]fluoreno[3,2-b]pyrans via diradicals generated from 1-(2-(4-(2-alkoxyethylphenyl)butan-1,3-diynyl))phenylpetan-2,4-diyn-1-ols and trapping evidence for the 1,2-didehydrobenzene diradical. Tetrahedron Lett. 38, 3943–3946 (1997).
Bradley, A.Z. & Johnson, R.P. Thermolysis of 1,3,8-nonatriyne: evidence for intramolecular [2+4] cycloaromatization to a benzyne intermediate. J. Am. Chem. Soc. 119, 9917–9918 (1997).
Tsui, J.A. & Sterenberg, B.T. A metal-templated 4 + 2 cycloaddition reaction of an alkyne and a diyne to form a 1,2-aryne. Organometallics 28, 4906–4908 (2009).
Kimura, H., Torikai, K., Miyawaki, K. & Ueda, I. Scope of the thermal cyclization of nonconjugated ene-yne-nitrile system: a facile synthesis of cyanofluorenol derivatives. Chem. Lett. 37, 662–663 (2008).
Hoye, T.R., Baire, B., Niu, D., Willoughby, P.H. & Woods, B.P. The hexadehydro-Diels-Alder reaction. Nature 490, 208–212 (2012).
Jork, H., Funk, W., Fischer, W. & Wimmer, H. Thin-layer Chromatography Reagents and Detection Methods; Vol. 1a: Physical and Chemical Detection Methods: Fundamentals, Reagents I. (VCH, 1990).
Still, W.C., Kahn, M. & Mitra, A. Rapid chromatographic technique for preparative separations with moderate resolution. J. Org. Chem. 43, 2923–2925 (1978).
Brandsma, L. Halogenation of acetylenes. in Synthesis of Acetylenes, Allenes and Cumulenes: Methods and Techniques, 191–202 (Elsevier, 2004).
Wenk, H.H., Winkler, M. & Sander, W. One century of aryne chemistry. Angew. Chem. Int. Edn. 42, 502–528 (2003).
Nicolaou, K.C., Snyder, S.A., Montagnon, T. & Vassilikogiannakis, G. The Diels-Alder reaction in total synthesis. Angew. Chem. Int. Edn. 41, 1668–1698 (2002).
Stoermer, R. & Kahlert, B. Ueber das 1- und 2-Bromcumaron. Ber. Dtsch. Chem. Ges. 35, 1633–1640 (1902).
Roberts, J.D., Simmons, H.E., Carlsmith, L.A. & Vaughan, C.W. Rearrangement in the reaction of chlorobenzene-1-C14 with potassium amide. J. Am. Chem. Soc. 75, 3290–3291 (1953).
Huisgen, R. & Rist, H. Über Umlagerungen bei nucleophilen Substitutionen in der aromatischen Reihe und ihre Deutung. Naturwissenschaften 41, 358–359 (1954).
Wittig, G. & Pohmer, L. Intermediäre Bildung von Dehydrobenzol (Cyclohexadienin). Angew. Chem. 67, 348 (1955).
Hoffmann, R.W. Dehydrobenzone and Cycloalkynes. Organic Chemistry, a Series of Monographs, Vol. 11 (Academic Press, 1967).
Kitamura, T. Synthetic methods for the generation and preparative application of benzyne. Aust. J. Chem. 63, 987–1001 (2010).
Yoshida, H., Ohshita, J. & Kunai, A. Aryne, ortho-quinone methide, and ortho-quinodimethane: synthesis of multisubstituted arenes using the aromatic reactive intermediates. Bull. Chem. Soc. Jpn. 83, 199–219 (2010).
Worlikar, S.A. & Larock, R.C. Pd-catalyzed reactions involving arynes. Curr. Org. Chem. 15, 3214–3232 (2011).
Gampe, C.M. & Carreira, E.M. Arynes and cyclohexyne in natural product synthesis. Angew. Chem. Int. Edn. 51, 3766–3778 (2012).
Tadross, P.M. & Stoltz, B.M. A comprehensive history of arynes in natural product total synthesis. Chem. Rev. 112, 3550–3577 (2012).
Bhunia, A., Yetra, S.R. & Biju, A.T. Recent advances in transition-metal-free carbon-carbon and carbon-heteroatom bond-forming reactions using arynes. Chem. Soc. Rev. 41, 3140–3152 (2012).
Okuma, K. Reaction of arynes with carbon-heteroatom double bonds. Heterocycles 85, 515–544 (2012).
Yoshida, H. & Takaki, K. Multicomponent coupling reaction of arynes for construction of heterocyclic skeletons. Heterocycles 85, 1333–1349 (2012).
Kovalev, I.S. et al. Aryne intermediates in the synthesis of polynuclear heterocyclic systems. Chem. Heterocycl. Compds. 48, 536–547 (2012).
Yoshida, H. & Takaki, K. Aryne insertion reactions into carbon-carbon -bonds. Synlett 23, 1725–1732 (2012).
Michael, A. & Bucher, J.E. Über die Einwirkung von Eissigsäureanhydrid auf Phenylpropiolsäure. Chem. Zentrblt 731–733 (1898).
Diels, O. & Alder, K. Syntheses in the hydroaromatic series. Justus Liebigs Ann. Chem. 460, 98–122 (1928).
Acknowledgements
D.N. and P.H.W. thank the University of Minnesota Graduate School Doctoral Dissertation Fellowship and the National Science Foundation Graduate Research Fellowship program, respectively. Financial support from the US National Institutes of Health (GM65597 and CA76497) is acknowledged.
Author information
Authors and Affiliations
Contributions
B.B., D.N., P.H.W., B.P.W. and T.R.H. contributed equally to developing the experimental procedures and writing the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Baire, B., Niu, D., Willoughby, P. et al. Synthesis of complex benzenoids via the intermediate generation of o-benzynes through the hexadehydro-Diels-Alder reaction. Nat Protoc 8, 501–508 (2013). https://doi.org/10.1038/nprot.2013.017
Published:
Issue Date:
DOI: https://doi.org/10.1038/nprot.2013.017
This article is cited by
-
A review of self-healable natural rubber based on reversible bonds: fundamental, design principle and performance
Journal of Materials Science (2023)
-
The aromatic ene reaction
Nature Chemistry (2014)
-
Alkane desaturation by concerted double hydrogen atom transfer to benzyne
Nature (2013)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.